- Pope Et Al-2001-Arthritis & Rheumatism

7/26/2019 - Pope Et Al-2001-Arthritis & Rheumatism

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ARTHRITIS & RHEUMATISMVol. 44, No. 6, June 2001, pp 13511358 2001, American College of RheumatologyPublished by Wiley-Liss, Inc.

A Randomized, Controlled Trial of Methotrexate Versus

Placebo in Early Diffuse Scleroderma

Janet E. Pope,1 Nicholas Bellamy,2 James R. Seibold,3 Murray Baron,4 Michael Ellman,5

Simon Carette,6 C. Douglas Smith,7 Ian M. Chalmers,8 Paul Hong,1 David OHanlon,9

Elzbieta Kaminska,10 Janet Markland,11 John Sibley,12 Luis Catoggio,13 and Daniel E. Furst14

Objective. Early diffuse scleroderma (systemic

sclerosis; SSc) has no proven treatment. This study was

undertaken to examine the efficacy of methotrexate

(MTX) in improving the skin and other disease para-

meters in early diffuse SSc.Methods.Seventy-one patients with diffuse SSc of


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defined as SSc with skin involvement distal to the elbowsor knees, with or without involvement of the face.Diffuse cutaneous SSc (dcSSc) involves sclerodermatousskin changes proximal to the elbows or knees, with acraland truncal involvement (2). SSc is difficult to treat, and

there is high mortality associated with the diffuse formof the disease. Prominent visceral involvement is a riskfactor for increased morbidity and mortality. Patients

with early dcSSc are reported to have a 2034% 5-yearsurvival rate (3,4). The efficacy of D-penicillamine (D-Pen), an established treatment for SSc, is questionable:a randomized, controlled trial of conventional-dose ver-sus low-dose D-Pen demonstrated no benefit with eitherdosage (5). Cyclosporin A (CsA) has been used experi-mentally as a treatment of SSc; patients receiving thistherapy have had decreased skin scores, but this isfrequently accompanied by a reduction in renal function.In one pilot study, the skin score decreased by 35% in6 of 10 patients after 48 weeks of CsA treatment, but theserum creatinine level increased in 7, and hypertensionoccurred in 2 (6). There have been no randomized,controlled trials of CsA in early dcSSc, and thus there isno proof of its efficacy.

Methotrexate (MTX) is a folic acid analog thatacts as a competitive antagonist of folic acid reductase.In one study (7), dermal fibroblasts from 9 patients withSSc and 9 controls were cultured with MTX, and glycos-aminoglycan (GAG) synthesis was measured. GAG syn-thesis increased in both normal and scleroderma fibro-blasts with increasing concentration of MTX; therefore,

the potential mechanism of action of MTX on fibro-blasts is not due to inhibition of GAG synthesis (7).In two uncontrolled case series, MTX treatment

in scleroderma was successful, both in improving thehealing of digital ulcers and in causing softening of theskin (8,9). In a blinded, placebo-controlled, crossovertrial of intramuscular MTX in limited and diffuse SSc,the active treatment group responded better than theplacebo group at 6 months, based on preferred responsecriteria and skin score (P 0.06), but the patient groups

were small (n 12 in the placebo group and 17 in theMTX group) (9). The trial continued for 1 year, but mostpatients who initially took MTX chose not to participate

in the placebo phase, so the randomized, blinded trialdata that were available pertained to only 6 months. Inthat trial, the proportion of men was higher in the MTXgroup than in the placebo group, which may have biasedthe results against MTX since SSc may be more severe inmen than in women (10). In addition, the disease courseand responsiveness to treatment may be very different inlcSSc compared with dcSSc.

The efficacy of MTX in the treatment of earlydiffuse SSc has not previously been investigated in alarge controlled trial. This report describes a multi-center, randomized, placebo-controlled, double-blindtrial of MTX therapy for early dcSSc.

PATIENTS AND METHODS

This study received approval from all participatingethics committees and/or institutional review boards (IRB).Subjects were recruited from 8 centers after informed consentwas obtained. Initially, we performed a pilot project to deter-mine the means and standard deviations, in other patients withdcSSc, of the outcome measures used in our study, to allow foraccurate sample size calculation (11). Prior to enrollment ofpatients into the trial, the Canadian investigators met tostandardize the outcome measures in order to decrease inter-observer variability (12). The study was a 1-year, double-blind,parallel trial in which the patient and the outcome assessor did

not know the treatment assignment. The outcome assessor wasalso unaware of any side effects that the patient was experi-encing or any laboratory abnormalities the patient may havehad. The toxicity evaluator was also blinded and was not thesame person as the outcome assessor.

The patients were enrolled in a randomized mannerwith balanced blocks of 4, and were stratified within eachcenter. The randomization was done in advance centrally, andthe medication was sent at the time of trial entry. Clinicians atthe participating centers had no way of breaking the codelocally. However, for safety reasons, in an emergency, theycould call the site of the principal investigator and have thecode broken.

Patients could be included in the study if they wereoutpatients age18 years, were practicing an effective form of

contraception if female, they fulfilled the American College ofRheumatology (formerly, the American Rheumatism Associ-ation) preliminary criteria for scleroderma (13), they haddiffuse scleroderma as described by LeRoy et al (2), theirscleroderma had been diagnosed within the last 3 years andtheir skin involvement had also developed within the last 3years, and they had a University of California, Los Angeles(UCLA) skin score (14) of at least 5 (maximum possiblescore 30). Exclusion criteria were as follows: 1) overlapsyndrome, mixed connective tissue disease, morphea, or linearscleroderma; 2) contraindication to MTX treatment, such asaspartate transaminase (AST) or bilirubin level 2 times theupper limit of normal, confirmed upon repeat testing; 3)ingestion of2 alcoholic drinks per week; 4) presence of anychronic liver disease; 5) insulin-dependent diabetes mellitus; 6)any serious coexisting illness or history of malignancy otherthan skin cancer; 7) current or past use of MTX; 8) moderaterestrictive pulmonary disease, or forced expiratory volume in 1second or carbon monoxide diffusing capacity (DLCO) 40%of predicted; 9) hemoglobin 90 gm/liter; 10) white blood cellcount 3.5 109/liter; 11) platelet count 150 109/liter; 12)serum creatinine 200 moles/liter; 13) pregnancy; 14) lacta-tion or not practicing birth control where appropriate; 15)receiving immunosuppressive therapy currently or within thelast 3 months (including D-Pen or any other antimetabolites);

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16) receiving prednisone at a dosage of15 mg/day or othercorticosteroids at an equivalent dosage. Patients who hadpreviously taken steroids and were no longer taking them hadto have discontinued steroid treatment at least 2 monthsbefore trial entry. The steroid dosage had to have been stablewithin the last 2 months. Those with uncontrolled hypertension

(blood pressure 160/100 mm Hg upon repeat measurement)or with severe congestive heart failure were also excluded.

The 2 primary outcome measures were 1) the skinscore as measured by 2 different techniques (the UCLA skinscore [10 sites with a maximum possible score for tethering of3 at each site] [14], and the modified Rodnan score [26 skinregions scored from 0 to 3 for skin tethering] [15]) and 2) theoutcome assessors global assessment as recorded on a 10-cmvisual analog scale (VAS). The secondary outcome measureswere the Health Assessment Questionnaire disability and painscores (16), functional index (17), patient global assessment(measured on a 10-cm VAS), DLCO (% predicted), physicalparameters including grip strength, oral opening, and flexionindex, the presence of renal crisis, and mortality. Theseoutcome measures were thought to be underpowered in the

sample size calculations and thus were used as secondarymeasures. With only 3 parameters for primary outcome (2 skinscores and 1 global assessment) and no scheduled interimanalysis, we did not consider there to be a need to correct formultiple statistical tests. The outcome measurements wereperformed at baseline and then every 3 months for 1 year. Theresults were based on an intent-to-treat analysis, so patientswho discontinued the study medication were encouraged tocontinue with their followup visits.

The placebo tablets were identical in color and taste totablets of 2.5 mg of MTX but contained inert ingredients. Bothplacebo and MTX were supplied by David Bull Laboratories(Montreal, Quebec, Canada). The initial dosage was 4 tabletsper week (i.e., those taking MTX began with 10 mg per week)divided over a 48-hour period. At 2 centers, patients received

1.252.5 mg of active MTX once a week in addition to theirstudy medication. This was done to meet the requirements ofthe IRB and to enhance recruitment. These patients (11 in theplacebo group and 11 in the active treatment group) werecombined with the other subjects, such that the placebo groupincluded 11 patients who were actually receiving placebo plus1.252.5 mg of MTX per week, and the MTX group included11 patients receiving a total of 16.2517.5 mg of MTX perweek. Monthly for the first 2 months, the dosage was increasedby 1 tablet, up to a total of 6 tablets per week (i.e., 15 mg perweek of MTX or 6 placebo tablets per week) in the thirdmonth. The number of tablets was increased for all subjects tomaintain blinding. This dosage was maintained throughout thestudy if it was tolerated. The protocol allowed for appropriatedosage reductions if side effects or adverse events occurred.

At baseline, chest radiography and pulmonary functiontesting were performed. Pulmonary function testing was re-peated at 12 months. At each visit, information on side effectswas elicited by open questions, and then a specific side effectform was completed by the patient. Laboratory testing includ-ing a complete blood cell count and liver enzyme testing (AST,alkaline phosphatase, and bilirubin) was performed every 2weeks for the first 3 months and then monthly thereafter.Creatinine testing and urinalysis were performed every 3months. Extra tests were performed as needed, such as when

there were significant laboratory abnormalities that may havebeen related to the study medication. Folic acid was prescribedat the discretion of the toxicity monitor, but was used rarely.Criteria for withholding or reducing the study drug includedside effects and laboratory abnormalities. There were criteriafor temporary and permanent discontinuation, for reversible

or more serious adverse effects, respectively. At each visit,compliance was monitored with pill counts. Patients were seenby the outcome assessor every 3 months and by the toxicityassessor at least every 3 months. Patients could continue toreceive any standard therapy, such as calcium channel block-ers, vasodilators, gastric motility drugs, antireflux therapy,antihypertensive agents, analgesics, and occupational andphysical therapy. New medication was recorded for each trialparticipant.

All statistical tests were 2-tailed. Pvalues less than 0.05were considered significant. Comparisons were between-groupdifferences unless otherwise stated. A repeated-measures ana-lysis compared the mean scores for the predetermined out-come measures at baseline and at 3, 6, 9, and 12 months in theactive treatment and placebo groups. The analyses were per-

formed using actual data and intent-to-treat data. Thus, forpatients who discontinued treatment and failed to return forfurther visits, the last known values for the outcome measureswere carried forward. The differences from baseline to 12months (change scores) for primary and selected secondaryoutcome measures were compared between the 2 groups.Logistic regression analysis was performed to adjust for base-line differences in characteristics that could be important, suchas sex and prednisone use. A post hoc analysis was done todetermine numbers of responders in each (those who had atleast a 20% improvement in skin score, global assessment,and/or DLCO). The sample size needed for detection of a 35%difference in skin score (a change of 3 units in the UCLA skinscore) was 36 per group assuming a loss to followup of 15%,with a 2-tailed of 0.05 and a of 0.2.

RESULTS

A total of 71 patients were enrolled in the study.Thirty-five were randomized to receive MTX and 36 toreceive placebo. The mean SEM age was 47.0 2.2

years in the MTX group and 48.8 2.4 years in theplacebo group. The proportion of men was higher in theplacebo group (8 of 36, versus 4 of 35 in the MTX group;P 0.22). The average disease duration was 6.3 monthsin the MTX group and 7.3 months in the placebo group(P 0.5).

Baseline characteristics of the patients in eachgroup are shown in Table 1. Prednisone use at baseline

was more common in the placebo group (10 patients inthe MTX group and 25 in the placebo group werecurrently taking prednisone or had in the past; P 0.005). Ten patients in the MTX group and 7 in theplacebo group had used D-Pen (P 0.3). Skin scores

were similar in the 2 groups (mean SEM UCLA

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score 10.9 1.0 in the MTX group versus 11.3 0.8 inthe placebo group [P 0.7]; modified Rodnan score27.7 2.4 in the MTX group versus 27.4 2.0 in theplacebo group [P 0.9]). There were no statistically

significant differences between groups for other re-ported baseline characteristics, but the DLCO wasslightly better in the active treatment group (77.5%

versus 70.6%; P 0.14).The 22 patients who received additional MTX

(half a tablet or 1 tablet extra per week) were similar tothe group as a whole with respect to baseline character-istics and final outcome measure results. For example,baseline skin scores of patients at the 2 centers wherethis was done were as follows: UCLA score 8.8 and 11.6in the active treatment group and the placebo group,respectively, and modified Rodnan score 25.1 and 29.2,respectively; at 12 months, these values were as follows:

UCLA score 6.2 and 10.1 in the active treatment groupand the placebo group, respectively, and modified Rod-nan score 17.6 and 26.4, respectively. Thus, these pa-tients were included in the appropriate groups (placeboor active treatment) for data analysis.

The trial data on patients who completed treat-ment (i.e., not intent-to-treat data) for the primaryoutcome measures are shown in Table 2. The placebo

group had worse UCLA skin scores at 3 months(mean SEM 15.8 3.2, versus 10.3 1.2 in the MTXgroup; P 0.05), but by 6 months and 9 months the gaphad narrowed, and at 12 months the UCLA scores in the

MTX and placebo groups, respectively, were 8.8

1.2and 11.0 0.9 (P 0.15). Similarly, the modifiedRodnan skin score improved at 3 months and continuedto improve in the MTX-treated patients, but the differ-ence from the placebo group did not reach statisticalsignificance (P 0.17 at 12 months). The physicianglobal assessment (10-cm VAS) was slightly worse atbaseline in the placebo group (5.8 0.4, versus 5.1 0.4in the MTX group; P 0.21); at 6 months this assess-ment favored the MTX group, though not significantly(4.5 0.4 in the MTX group versus 5.3 0.4 in theplacebo group; P 0.20), and at 12 months the differ-ence was statistically significant (4.2 0.5 and 5.5 0.4

in the MTX and placebo groups, respectively; P 0.035). However, only 54 patients were evaluated by thismeasure at the end of the trial. In some cases, data weremissing, so the n values for the outcome measures variedslightly.

Table 3 presents the data on secondary outcomesfor all patients who completed the trial. As was ex-pected, none of these secondary outcome measures

Table 1. Baseline characteristics of the 71 scleroderma patients, by treatment group*

Methotrexate

(n 35)

Placebo

(n 36) P

Age, years 47.0 2.2 48.8 2.4 0.80No. male/no. female 4/31 8/28 0.22

Disease duration, months 6.3 1.0 7.3 1.1 0.50Prednisone use (current/past/never), no. 2/8/25 12/13/11 0.005D-penicillamine use, no. 10 7 0.30UCLA skin scores, 030 10.9 1.0 11.3 0.8 0.71Modified Rodnan skin scores, 0 78 27.7 2.4 27.4 2.0 0.91MD global assessment, 10-cm VAS 5.1 0.4 5.8 0.4 0.21Patient global assessment, 10-cm VAS 4.5 0.3 5.2 0.4 0.15Digital ulcers, no. with 9 8 0.12No. of digital ulcers 0.4 0.2 0.5 0.2 0.69Oral opening, mm 40.1 2.0 37.6 2.2 0.38HAQ pain, 03 1.6 0.1 1.1 0.1 0.78HAQ disability, 03 1.4 0.1 1.2 0.1 0.48Functional index, 033 8.4 1.0 8.0 1.1 0.81Grip strength, mm Hg

Right 139 11.3 152 10.0 0.37Left 135 11.4 147 9.9 0.42

Flexion index, mm

Right 63.0 6.8 66.7 6.9 0.70Left 61.2 7.0 65.0 6.9 0.70

DLCO % predicted 77.5 3.6 70.6 3.0 0.14

* Except where otherwise indicated, values are the mean SEM. UCLA University of California, LosAngeles; VAS visual analog scale; HAQ Health Assessment Questionnaire; DLCO carbonmonoxide diffusing capacity.

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showed a statistically significant difference betweenthe 2 treatment groups. Interestingly, the patientglobal assessment of disease activity was almost identicalin the 2 groups at the end of the trial (4.2 0.4 and4.3 0.4 in the MTX and placebo groups, respectively;P 0.8). The DLCO was better preserved in the MTXgroup, but not significantly so (75.7% in the MTX groupand 61.8% in the placebo group; P 0.2). When theDLCO was adjusted by the baseline value, there was asignificant difference favoring MTX (P 0.0001).

Thirteen patients assigned to the MTX group and11 assigned to the placebo group dropped out prior tostudy completion (P 0.6). In both groups, most

dropouts were due to treatment inefficacy. Only 1patient dropped out due to an adverse event (oral ulcers,in an MTX-treated patient). There were more deathsduring the trial and the followup period (median fol-

lowup 1.5 years) in the placebo group (7 patients) thanin the MTX group (3 patients) (P 0.18).

Table 4 shows the results of the intent-to-treatanalysis, in which the last known data points were

carried forward for all patients. There were some statis-tically significant between-group differences at 12months, and the significance remained fairly constant

with adjustment for baseline scores of the variablemeasured and for differences in sex distribution andcurrent prednisone use at baseline. However, the clinicaldifferences were small.

We also examined change scores (from baselineto 12 months) with intent-to-treat methodology, com-

paring between-group differences. The skin scores im-proved by 10% with MTX and worsened by 10%

with placebo. The change in UCLA skin score was1.23 with MTX versus 1.22 with placebo (P 0.02);for the modified Rodnan skin score it was 4.3 withMTX versus 1.8 with placebo (P 0.009). The DLCOshowed a worsening of 3.7% with MTX compared

with 7.8% with placebo (P 0.14). Physician globalassessment improved by only 0.2 and 0.3 in the MTX andplacebo groups, respectively (P 0.9). After adjustmentfor differences in sex distribution and baseline pred-nisone use, the change in the UCLA skin score almost

reached significance (P

0.07), and the change in themodified Rodnan score was significant (P 0.03).Figures 1AD illustrate the number of patients

showing improvement in skin scores, physician globalassessment, and DLCO. With regard to the UCLA skinscore (Figure 1A), 9 MTX-treated patients and 13placebo-treated patients had no improvement, 6 and 4,respectively, had 120% improvement, 8 and 5, respec-

Table 2. Results for primary outcome measures during 12 months of treatment, in patients receiving methotrexate or placebo*

Months

0 3 6 9 12

UCLA skin score, 030

Methotrexate 10.9

1.0 (35) 10.3

1.2 (29) 9.1

1.2 (28) 9.2

1.2 (28) 8.8

1.2 (27)Placebo 11.3 0.8 (36) 15.8 3.2 (33) 11.9 1.0 (29) 10.9 1.1 (25) 11.0 0.9 (24)P 0.7 0.05 0.08 0.29 0.15

Modified Rodnan skin score, 078Methotrexate 27.7 2.4 (35) 25.8 2.9 (30) 22.7 2.8 (28) 22.0 2.9 (28) 21.4 2.8 (27)Placebo 27.4 2.0 (36) 28.8 2.1 (34) 27.9 2.4 (29) 27.7 2.5 (27) 26.3 2.1 (24)P 0.91 0.40 0.15 0.14 0.17

MD global assessment, 10-cm VASMethotrexate 5.1 0.4 (35) 5.1 0.4 (29) 4.5 0.4 (28) 4.9 0.5 (27) 4.2 0.5 (25)Placebo 5.8 0.4 (35) 5.8 0.3 (33) 5.3 0.4 (28) 5.3 0.4 (25) 5.5 0.4 (29)P 0.21 0.15 0.20 0.47 0.035

* Values are the mean SEM (n). See Table 1 for definitions.

Table 3. Results for secondary outcome measures at 12 months, in

patients receiving methotrexate or placebo*

Methotrexate Placebo P

Oral opening, mm 38.7 2.3 (26) 35.1 2.5 (23) 0.3HAQ pain, 03 1.1 0.1 (24) 1.0 0.2 (22) 0.9HAQ disabi lity, 0 3 1.2 0.2 (24) 1.2 0.2 (22) 0.9Functional index, 033 8.3 1.2 (26) 7.5 1.4 (24) 0.7Grip strength, mm Hg

Right 160 14 (26) 146 14 (24) 0.5Left 156 13 (26) 142 14 (24) 0.5

Flexion index, mmRight 68 8 (26) 84 10 (24) 0.2Left 65 8 (26) 82 10 (24) 0.2

DLCO, % predicted 75.7 4.6 (27) 61.8 3.4 (26) 0.2Patient global

assessment, 10-cmVAS

4.2 0.4 (26) 4.3 0.4 (28) 0.8

* Values are the mean SEM (n). See Table 1 for definitions.



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tively, had 2150% improvement, and 3 and 2, respec-tively, had 5170% improvement; 71100% improve-ment was observed in 1 MTX-treated patient. For themodified Rodnan skin score (Figure 1B), 9 patients inthe MTX group and 12 in the placebo group had noimprovement, 5 and 3, respectively, had 120% improve-

ment, 10 and 8, respectively, had 2150% improvement,and 3 and 1, respectively, had 5170% improvement.The clinical trend seemed to favor MTX. As shown inFigure 1C, 10 patients receiving MTX and 15 receivingplacebo had no improvement in the physician globalassessment, whereas 11 and 9, respectively, showed2150% improvement. Again, the numbers seemed tofavor active treatment, but not impressively so. TheDLCOshowed no improvement or a 10% improvementin 13 MTX-treated and 12 placebo-treated patients.Improvement in the DLCOof10% was observed in 14patients in the MTX group and 14 in the placebo group.These data indicate that MTX had no obvious effect

compared with placebo in terms of proportions ofresponders.

DISCUSSION

MTX has proven useful in graft-versus-host dis-ease, which has some similarities to scleroderma (18). In2 case series, MTX appeared promising in SSc. In the

series reported by Bode et al, 10 patients (8 with diffuseand 2 with limited disease) were treated with MTX (8).None of the patients had progression of skin involve-ment during the study period of 538 months. Ninepatients had improvement in skin induration; the im-provement was characterized as marked in 3, moderate

in 2, and mild in 4. One patient had no change in skinscore. One had a dramatic improvement in pulmonary

function as measured by a 50% improvement in theDLCO. The weekly dosages of 7.550 mg were welltolerated. In the series studied by van den Hoogen et al(19), 8 patients were treated for 1 year with MTX at 15mg/week. The total skin score decreased by a mean of50%, but there was no effect on internal organ functionexcept for a slight decrease in creatinine clearance.

Our results do not provide strong support for thenotion that MTX is an effective treatment in early

diffuse scleroderma. However, some early differences

observed in the UCLA skin score persisted throughoutthe trial. We are uncertain whether the slight trend infavor of MTX would continue in a longer study, andperhaps a greater effect of MTX would have been seenhad the dosage been higher. The dosage of MTX used

was considered high at the time the trial was designed,but is now considered moderate. Statistically, if the datacontinued in the same manner, our results would have

Table 4. Results for selected outcome measures during the 12-month trial, by intent-to-treat analysis, in patients receiving methotrexate orplacebo*

Months

0 3 6 9 12

UCLA skin score, 030Methotrexate 10.9 1.0 10.6 1.0 10.0 1.0 10.1 1.0 9.6 1.0Placebo 11.3 0.8 12.9 1.0 12.4 1.0 12.1 1.0 12.6 1.0P 0.71 0.10 0.08 0.16 0.04

Modified Rodnan skin score, 078Methotrexate 27.7 2.4 26.5 2.5 24.7 2.4 24.4 2.5 23.6 2.4Placebo 27.4 2.0 29.1 2.0 28.7 2.0 28.5 2.1 29.2 2.1P 0.92 0.41 0.20 0.21 0.09

MD global assessment, 10-cm VASMethotrexate 5.1 0.4 5.2 0.4 4.8 0.4 5.2 0.4 4.9 0.4Placebo 5.8 0.4 5.7 0.3 5.4 0.4 5.6 0.4 5.6 0.4P 0.21 0.30 0.26 0.45 0.28

Patient global assessment, 10-cm VASMethotrexate 4.5 0.3 4.3 0.3 4.6 0.3 4.6 0.4 4.5 0.4Placebo 5.2 0.4 5.2 0.3 5.0 0.4 5.1 0.4 4.8 0.4P 0.15 0.05 0.40 0.35 0.58

DLCO, % predicted

Methotrexate 77.5 3.6 73.8 4.0Placebo 70.6 3.0 62.9 2.9P 0.14 0.03

* Values are the mean SEM. See Table 1 for definitions. Tested at 0 and 12 months only.

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only had 50% power to detect a between-group differ-ence if a real difference existed.

The beneficial effect of MTX on the severity ofskin involvement, seen early in the trial, did not increase

very much after a few months. The early improvementmay have reflected an antiinflammatory effect of MTX,perhaps reducing edema. Because the results with MTXseemed slightly better than those with placebo, ourinterpretation of the data may have been different,

favoring MTX, if the trial had been terminated at 6months. However, the improvement in skin score in theMTX group was only 20% at best.

The intent-to-treat data showed more favorableresults for MTX compared with placebo. However, theplacebo and active treatment groups may not have beenfully comparable. The patients in the placebo group

were slightly older, and perhaps sicker at baseline as

indicated by the higher frequency of steroid use. Inaddition, there was a higher percentage of males in theplacebo group, and male sex may be related to worseoutcome (10). Perhaps, therefore, the trends favoringMTX may have been due to confounding factors. Theoutcome measures chosen may be too insensitive tochange to detect a meaningful difference. Interestingly,patient global assessments were not better in the MTXgroup compared with the placebo group.

In an earlier study of MTX versus placebo in SSc(9), only the first 6 months can be analyzed as arandomized, controlled trial. Patients in both treatmentgroups in that study had equally early disease, but manyhad limited involvement, especially in the MTX group(12 patients, versus 6 in the placebo group). This mayhave biased the data in favor of MTX, because disease isgenerally less severe in lcSSc. The baseline skin scores in

Figure 1. Number of scleroderma patients in the methotrexate (MTX)treated group (active) and the placebo-treated group showing improvement

in the University of California, Los Angeles (UCLA) skin score (A),the modified Rodnan skin score (B),the physician global assessment (C),and

the diffusing capacity for carbon monoxide (DLCO) (D). The values for percent improvement were generated using baseline and treatment-

termination data. For both skin scores as well as for the physician global assessment, more patients in the MTX group than in the placebo groupshowed improvement; however, the differences between groups were not significant. For DLCO, values at baseline and treatment termination were

similar in the two groups, and there was no trend that seemed to favor one group.



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that trial were 20.2 and 20.7 in the MTX group and theplacebo group, respectively. The skin score decreasedminimally in the MTX group at 6 months (0.7),compared with an increase of 1.2 in the placebo group(P 0.06). These results would hardly be deemed

clinically relevant. The findings in the present study areconsistent with the results of that trial.

Questions remain about MTX treatment ofscleroderma, with respect to dosage, route of adminis-tration and resultant absorption, and duration of use,any of which may have been inappropriately chosen inthe present trial. However, the data generated from thistrial do not provide strong support for the use of MTXto improve skin involvement or overall clinical status inearly diffuse SSc. An effective treatment of this progres-sive disease is needed, other agents should be investi-gated in well-conducted randomized, blinded trials.

ACKNOWLEDGMENT

We are grateful to David Bull Laboratories (Montreal,Quebec, Canada) for providing MTX and placebo.

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2. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T,Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classifica-tion, subsets and pathogenesis. J Rheumatol 1988;15:2024.

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den Berg WB, van Lier HJJ, van de Putte LBA. Effects ofmethotrexate on glycosaminoglycan production by sclerodermafibroblasts in culture. Ann Rheum Dis 1993;52:75861.

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